Nitric oxide donor compounds (NO donors) have been used for many years in the treatment of various clinical conditions, particularly coronary artery disease. (Harrison, D. G. and Bates, J. N. (1993) The nitrovasodilators: new ideas about old drugs. Circulation 87, 1461-1467.) They cause vasodilation, inhibit platelet aggregation, diminish myocardial contractile force and counteract thromboxane A2. (Bing, R. J., Yamamoto, T., Yamamoto, M., Kakar, R. and Cohen, A. (1999) New look at myocardial infarction: toward a better aspirin. Cardiovasc Res 43, 25-31.) The NO releasing ability of these compounds is due to nitrate functionality within the molecule. A nitroso functional group is present in all NO donor compounds. Some of these compounds need biochemical conversion, or biotransformation, of the nitrate group to NO. (Torfgard, K. E. and Ahlner, J. (1994) Mechanisms of action of nitrates. Cardiovasc Drugs Ther 8, 701-717.) The duration of their activity in vivo also varies. The oxidation products of NO are NO2xe2x88x92 and NO3xe2x88x92, collectively referred to as NOx. Many of the existing NO donors must be administered intravenously, which results in rapid onset of decreasing blood pressure accompanied by unwanted side effects. Their effect does not extend beyond the period of infusion. Another undesirable side effect of some NO donors includes an increase in heart rate. A need exists for an NO donor compound to treat disease that does not affect blood pressure or heart rate.
The invention is directed to a novel genus of compounds that are particularly useful as nitric oxide donors, as well as to methods of treatment using these compounds. In one embodiment, the invention is directed to a composition comprising a compound of the formula: 
wherein R is (CH2)n, wherein n ranges from 1 to 8 and wherein each hydrogen atom on the alkylene group and on the phenyl groups are optionally replaced by a substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, and hydroxy groups. Preferably the composition comprises the compound 3-(nitrooxymethyl)phenyl 2-hydroxybenzoate, referred to as B-NOD, of the formula: 
The compounds of the invention are useful as nitric oxide donor compounds that can be administered orally and that do not affect blood pressure or heart rate. It has been discovered that B-NOD generates NO in vivo and in vitro in a concentration- or dose-dependent manner. It is likely that NO release is enzymatically catalyzed, consistent with the findings that in vitro NO release is augmented by the presence of living cells, including blood platelets.
The invention is also directed to methods of treatment utilizing the above compounds. In one embodiment, the invention is directed to a method for treating coronary artery disease comprising administering a pharmaceutically-acceptable amount of a composition as described above to a patient in need thereof. These compositions are particularly useful for treating coronary artery disease following myocardial infarction because they influence contractility and metabolic function of the infarcted heart and reduce infarct size. In addition, these compounds are useful for counteracting thromboxane, inhibiting platelet activation, stimulating pro stanoids through activation of cyclooxygenase, reducing myocardial contractility, attenuating inotropic response, reducing cardiac lactate accumulation by forming cGMP, dilating coronary arteries, and suppressing ventricular fibrillation. These compounds may also be useful for treating or preventing strokes or embolism.
Notably, B-NOD is active for up to seven hours following administration. B-NOD inhibits platelet aggregation through stimulation of guanalate cyclase, increases cyclic guanosine monophosphate (cGMP) production in a dose-dependent manner, causes the release of prostanoids, causes vasodilation, affects angiogenesis, and produces oxygen free radicals.
B-NOD has significant advantages over other NO donor compounds. Compared to nitroglycerin (American Radiolabeled Chemicals, Inc. St. Louis, Mo.), B-NOD releases NO for much longer periods, does not cause a decrease in blood pressure, and is only a partial pro-drug because it releases NO only after biotransformation of the nitrite group to NO. (Robertson, R. M. and Robertson, D. (1996) in The pharmacological basis of therapeutics (Goodman and Gilman, eds.), 9th ed., pp. 759-779, McGraw-Hill, New York.) B-NOD has longer action than the NO donor FR144420, (+/xe2x88x92)xe2x80x94Nxe2x80x94[(E)-4-Ethyl-3-[(Z)-hydroxyimino]-5-nitro-3-hexen-1- yl]-3-pyridinecarboxamide, (Fujisawa Pharmaceutical Co., Osaka, Japan), and does not affect blood pressure. (Kita, Y., Ohkubo, K., Hirasawa, Y., Katayama, Y., Ohno, M., Nishino, S., Kato, M. and Yoshida, K. (1995) FR144420, a novel, slow, nitric oxide-releasing agent. Eur J Pharmacol 275,125-130.) Compared to B-NOD, the NO-aspirin compound NCX 4016,2-acetoxybenzoate-2(1 nitroxy-methyl)-phenylester (AstraZeneca, Sxc3x6dertxc3xa4lje, Sweden), of the formula: 
has aspirin-like qualities that are undesirable in some circumstances, namely, inhibition of the isoenzymes cyclooxygenase-1 and cyclooxygenase-2 because of its aspirin moiety. (Cuzzolin L., Adami A., Degan M., Crivellente F., Bonapace S., Minuz P., Benoni G. Effect of single and repeated of anew nitroderivative of acetylsalicylic acid on platelet TXA2 production in rats. Life Sci 38:207-210, 1996.)
B-NOD does not cause a decrease in heart rate or an increase in blood pressure after administration, significant advantages over other NO donor compounds. B-NOD can be administered orally, unlike other NO donor compounds that must be administered intravenously, such as sodium nitroprusside (SNP) (Bates, J. N., Baker, M. T., Guerra, R., Jr. and G., H. D. (1991) Nitric oxide generation from nitroprusside by vascular tissue. Biochem Pharmacol 42(Suppl), S157-S165), SIN-1 (Arkonac, B. M., Kersten, J. R., Wynsen, J. C., Nijhawan, N. and Warltier, D. C. (1996) Differential hemodynamic effects of the nitric oxide donor pirsidomine in comparison to SIN-1, nitroprusside and nitroglycerin. Pharmacology 52, 92-100) and diethylenetriamine/nitric oxide (DETA/NO) (Takano, H., Tang, X. -L., Qiu, Y., Guo, Y., French, B. A. and Bolli, R. (1998) Nitric oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res 83, 73-84) (all available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.).